We have previously shown that coexpression of c-myc and transforming growth factor alpha (TGF-alpha) in transgenic mouse liver accelerates growth of tumors induced by either transgene alone. We now describe the consequences of constitutive expression of these transgenes on the kinetics of hepatocyte proliferation after partial hepatectomy (PH) in young adult c-myc monotransgenic and c-myc/TGF-alpha double transgenic mice. The results demonstrate that transgenic mice with liver specific expression of c-myc or c-myc plus TGF-alpha respond differently to PH. Constitutive expression of c-myc enhanced liver regeneration whereas coexpression of c-myc and TGF-alpha diminished proliferative response following PH. The c-myc/TGF-alpha transgenic mice displayed abnormalities of cell cycle progression associated with a senescent phenotype that includes a decreased rate of DNA synthesis accompanied by a decline in the steady-state levels of cyclins A and B mRNAs and a reduced replicative capacity of mature hepatocytes. These data suggest that prolonged and excessive stimulation of cell proliferation driven by coexpression of c-myc and TGF-alpha accelerates the normal process of liver aging. The c-myc/TGF-alpha transgenic mice may provide a model system for a replicative cellular senescence in vivo and its contribution to hepatic tumor development.